Original ResearchNovember 2022
A Nonlinear Mendelian Randomization Study
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    Visual Abstract. Vitamin D Deficiency Increases Mortality Risk in the UK Biobank.

    Low vitamin D levels have been associated with increased mortality, but randomized trials in participants with severe vitamin D deficiencies are lacking. This study used nonlinear Mendelian randomization to assess genetic evidence for the role of low vitamin D status in mortality.



    Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking.


    To assess genetic evidence for the causal role of low vitamin D status in mortality.


    Nonlinear Mendelian randomization analyses.


    UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010.


    307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data.


    Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020.


    There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L.


    Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate.


    Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels.

    Primary Funding Source:

    National Health and Medical Research Council.